The androgen receptor (AR) plays a central role in the progression of prostate cancer (Heinlein (2004)). Androgen ablation is highly effective in treating metastatic prostate cancer, though resistance inevitably develops leading to castrate-resistant prostate cancer (CRPC). Most cases of CRPC remain dependent on AR signaling, which has led to the clinical development and recent approval of potent AR-targeted therapies for CRPC (i.e., abiraterone, enzalutamide) (de Bono (2011); Scher (2012)). However, similar to first-generation anti-androgen therapies, patients develop resistance to these second-generation hormonal therapies. How CRPC tumors bypass AR signaling is emerging as a significant area of investigation.
In CRPC, crosstalk between estrogen- and androgen-signaling pathways may present an opportunity for clinical intervention. Estrogen receptor (ER) signaling through ER alpha (ERα) increases with prostate cancer progression (Ricke (2008); Clemson (2009); Rhodes (2007)) and can drive important oncogenic events, including TMPRSS2-ERG expression. Although ERα signaling has been extensively studied in breast cancer (Barwisck (2010); Best (2005); Glinsky (2004)), our understanding of the potential impact of this nuclear receptor on prostate physiology is less clear. Nevertheless, the connection is a particularly intriguing concept given that most cases of prostate cancer arise in the sixth decade of life, a time when testosterone levels are decreasing and estrogens are increasing in men. Mouse models suggest that antagonism of ERα may diminish prostate carcinogenesis (Ricke (2008))